scholarly journals Glioma cells require one-carbon metabolism to survive glutamine starvation

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Kazuhiro Tanaka ◽  
Takashi Sasayama ◽  
Hiroaki Nagashima ◽  
Yasuhiro Irino ◽  
Masatomo Takahashi ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Carbon Metabolism ◽  
Critical Role ◽  
Glioma Cells ◽  
Nutrient Utilization ◽  
Clinical Samples ◽  
Tumor Cell Death ◽  
Clinical Resistance ◽  
Glutamine Deprivation ◽  
One Carbon Metabolism

AbstractCancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. This metabolic process also includes redox maintenance and epigenetic regulation through nucleic acid and protein methylation, which enhance tumorigenicity and clinical resistance. However, less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we find that serine and glycine levels were higher in low-nutrient regions of tumors in glioblastoma multiforme (GBM) patients than they were in other regions. Metabolic and functional studies in GBM cells demonstrated that serine availability and one-carbon metabolism support glioma cell survival following glutamine deprivation. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate one-carbon metabolism. In clinical samples, MTHFD2 expression was highest in the nutrient-poor areas around “pseudopalisading necrosis.” Genetic suppression of MTHFD2 and autophagy inhibition caused tumor cell death and growth inhibition of glioma cells upon glutamine deprivation. These results highlight a critical role for serine-dependent one-carbon metabolism in surviving glutamine starvation and suggest new therapeutic targets for glioma cells adapting to a low-nutrient microenvironment.

TAMI-20. GLIOMA CELLS REPROGRAM SERINE-DEPENDENT ONE-CARBON METABOLISM TO SURVIVE GLUTAMINE STARVATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi202-vi202
Author(s):  
Kazuhiro Tanaka ◽  
Hiroaki Nagashima ◽  
Yuichi Fujita ◽  
Mitsuru Hashiguchi ◽  
Takashi Sasayama
Keyword(s):  
Cancer Cells ◽  
Carbon Metabolism ◽  
Glioma Cells ◽  
Nutrient Utilization ◽  
Clinical Samples ◽  
Tumor Cell Death ◽  
Functional Studies ◽  
Clinical Resistance ◽  
Glutamine Deprivation ◽  
One Carbon Metabolism

Abstract Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. This metabolic process also includes redox maintenance and epigenetic regulation through nucleic acid and protein methylation, which enhance tumorigenicity and clinical resistance. However, less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we find that serine and glycine levels were higher in low-nutrient regions of tumors in glioblastoma multiforme (GBM) patients than they were in other regions. Metabolic and functional studies in GBM cells demonstrated that serine availability and one-carbon metabolism support glioma cell survival following glutamine deprivation. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate one-carbon metabolism in GBM patient-derived sphere cells as well as in GBM cells. In clinical samples, MTHFD2 expression was highest in the nutrient-poor areas around “pseudopalisading necrosis.” Genetic suppression of MTHFD2 and autophagy inhibition caused tumor cell death and growth inhibition of glioma cells upon glutamine deprivation. These results may have important implications for serine-dependent one-carbon metabolism for glioma cells to survive glutamine starvation and suggest a new therapeutic strategy for patients with malignant glioma.

scholarly journals CBMS-07 SERINE SYNTHESIS AND ONE-CARBON METABOLISM IN GLIOMA CELLS TO SURVIVE GLUTAMINE STARVATION

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii6-ii6
Author(s):  
Kazuhiro Tanaka ◽  
Takashi Sasayama ◽  
Takiko Uno ◽  
Yuichi Fujita ◽  
Mitsuru Hashiguchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Carbon Metabolism ◽  
Metabolic Response ◽  
Glioma Cells ◽  
Nutrient Utilization ◽  
Clinical Samples ◽  
Clinical Resistance ◽  
Glutamine Deprivation ◽  
One Carbon Metabolism

Abstract Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. These metabolic processes also include redox maintenance and epigenetic regulation through nucleic acid and protein methylation, enhancing tumorigenicity and clinical resistance. But less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we identify a key role for serine availability and one-carbon metabolism in the survival of glioma cells from glutamine deprivation. To identify metabolic response to glutamine deprivation in glioma cells, we analyzed metabolites using gas chromatography and mass spectroscopy (GC/MS) in glioma cells cultured in glutamine-deprived medium and examined gene expression of key enzymes for one-carbon units using RT-PCR and western blotting methods. These expressions were also confirmed by immunohistochemical staining in glioma clinical samples Metabolome studies indicated serine, cysteine, and methionine as key differentiating amino acids between control and glutamine-deprived groups. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate serine synthesis and one-carbon metabolism. Importantly, suppression of this metabolite impaired glioma cell survival in glutamine deprivation. In human glioma samples. MTHFD2 expressions were highest in poorly nutrient regions around “pseudopalisading necrosis”. Serine-dependent one-carbon metabolism has a key role for glioma cells to survive glutamine starvation. These results may suggest the new therapeutic strategies targeting critical glioma cells adapting the tumor microenvironment.

scholarly journals CBMS-5 One-carbon metabolism protect glioma cells under glutamine starvation through upregulation of MTHFD2

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi2-vi3
Author(s):  
Kazuhiro Tanaka ◽  
Hiroaki Nagashima ◽  
Takiko Uno ◽  
Yuichi Fujita ◽  
Hirofumi Iwahashi ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Carbon Metabolism ◽  
Glioma Cells ◽  
Nutrient Utilization ◽  
Clinical Samples ◽  
Tumor Cell Death ◽  
Growth And Survival ◽  
Functional Studies ◽  
Glutamine Deprivation ◽  
One Carbon Metabolism

Abstract Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. However, less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we find that serine and glycine levels were higher in low-nutrient regions of tumors in glioblastoma multiforme (GBM) patients than they were in other regions. Metabolic and functional studies demonstrated that serine availability and one-carbon metabolism support glioma cell survival following glutamine deprivation. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate one-carbon metabolism. In clinical samples, MTHFD2 expression was highest in the nutrient-poor areas around pseudopalisading necrosis. Genetic suppression of MTHFD2 and autophagy inhibition caused tumor cell death and growth inhibition of glioma cells upon glutamine deprivation. These results suggest new therapeutic targets for glioma cells adapting to a low-nutrient microenvironment.

Extraction of ursolic acid from Ocimum sanctum and synthesis of its novel derivatives: effects on extracellular homocysteine, dihydrofolate reductase activity and proliferation of HepG2 human hepatoma cells

Pteridines ◽  
2013 ◽  
Vol 24 (3) ◽  
pp. 191-199 ◽  
Author(s):  
Apsara Batra ◽  
V. Girija Sastry
Keyword(s):  
Cancer Cells ◽  
Ursolic Acid ◽  
Dihydrofolate Reductase ◽  
Carbon Metabolism ◽  
Hepatoma Cells ◽  
Ocimum Sanctum ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Anti Cancer ◽  
One Carbon Metabolism

AbstractThe objective of the present study was to extract ursolic acid (UA) from Ocimum sanctum, to synthesize its bioactive derivatives, evaluate the anti-cancer effect of its derivatives and to establish the possible mechanism of action. In the present report, we extracted UA from whole plant of O. sanctum, synthesized its novel derivatives and investigated their effect on homocysteine metabolism and dihydrofolate reductase (DHFR) activity of HepG2 cells. UA and its derivatives UA-1, UA-2 and UA-3 down-regulated DHFR activity and increased extracellular homocysteine. UA-2 showed significant anti-proliferation activity in cancer cells. Cancer cells have increased the requirement of pyrimidine base thymidylate due to rapid cell division. Thymidylate biosynthesis depends on sufficient pools of folate dependent enzymes like DHFR. In the present study, we examined the UA and its derivatives mediated perturbation of DHFR activity and extracellular homocysteine in HepG2 human hepatoma cells. After incubation with UA-2, a potent inhibition of DHFR activity was observed. Our results showed that derivatization of UA might adversely affect DHFR activity. Measurement of extracellular homocysteine indicated impaired one-carbon metabolism in cells treated with UA derivatives. In conclusion, our data suggest an anti-cancer role of UA and its derivatives via inhibition of one-carbon metabolism.

scholarly journals CBMT-10. GLUTAMINE DEPRIVATION ALTERS ONE-CARBON METABOLISM TO MAINTAIN GLIOMA CELL SURVIVAL

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi34-vi34
Author(s):  
Kazuhiro Tanaka ◽  
Takashi Sasayama ◽  
Takiko Uno ◽  
Masahiro Maeyama ◽  
Yuichi Fujita ◽  
...  
Keyword(s):  
Cell Survival ◽  
Carbon Metabolism ◽  
Glioma Cell ◽  
Glutamine Deprivation ◽  
One Carbon Metabolism

scholarly journals Formate concentrations in maternal plasma during pregnancy and in cord blood in a cohort of pregnant Canadian women: relations to genetic polymorphisms and plasma metabolites

2019 ◽  
Vol 110 (5) ◽  
pp. 1131-1137 ◽  
Author(s):  
John T Brosnan ◽  
Lesley Plumptre ◽  
Margaret E Brosnan ◽  
Theerawat Pongnopparat ◽  
Shannon P Masih ◽  
...  
Keyword(s):  
Cord Blood ◽  
Early Pregnancy ◽  
Carbon Metabolism ◽  
Critical Role ◽  
Plasma Concentrations ◽  
Maternal Blood ◽  
Plasma Metabolites ◽  
Blood Samples ◽  
One Carbon Metabolism ◽  
Thymidylate Synthesis

ABSTRACT Background One-carbon metabolism, responsible for purine and thymidylate synthesis and transmethylation reactions, plays a critical role in embryonic and fetal development. Formate is a key player in one-carbon metabolism. In contrast to other one-carbon metabolites, it is not linked to tetrahydrofolate, is present in plasma at appreciable concentrations, and may therefore be distributed to different tissues. Objective The study was designed to determine the concentration of formate in cord blood in comparison with maternal blood taken earlier in pregnancy and at delivery and to relate formate concentrations to potential precursors and key fetal genotypes. Methods Formate and amino acids were measured in plasma during early pregnancy (12–16 wk), at delivery (37–42 wk), and in cord blood samples from 215 mothers, of a prospective cohort study. Three fetal genetic variants in one-carbon metabolism were assessed for their association with cord plasma concentrations of formate. Results The formate concentration was ∼60% higher in the cord blood samples than in mothers’ plasma. The maternal formate concentrations did not differ between the early pregnancy samples and those taken at delivery. Plasma concentrations of 4 formate precursors (serine, glycine, tryptophan, and methionine) were increased in cord blood compared with the maternal samples. Cord blood formate was influenced by fetal genotype, being ∼12% higher in infants harboring the MTHFR A1298C (rs1801131) AC or CC genotypes and 10% lower in infants harboring the MTHFD1 G1958A (rs2236225) GA or AA genotypes. Conclusions The increased formate concentrations in cord blood may support the increased activity of one-carbon metabolism in infants. As such, it would support increased rates of purine and thymidylate synthesis and the provision of methionine for methylation reactions.

scholarly journals TMEFF2 and SARDH cooperate to modulate one-carbon metabolism and invasion of prostate cancer cells

The Prostate ◽  
2013 ◽  
Vol 73 (14) ◽  
pp. 1561-1575 ◽  
Author(s):  
Thomas Green ◽  
Xiaofei Chen ◽  
Stephen Ryan ◽  
Adam S. Asch ◽  
Maria J. Ruiz-Echevarría
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Carbon Metabolism ◽  
Prostate Cancer Cells ◽  
One Carbon Metabolism

scholarly journals FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism

2021 ◽  
Author(s):  
Hyo Sub Choi ◽  
Ajay Bhat ◽  
Marshall B. Howington ◽  
Megan L. Schaller ◽  
Rebecca Cox ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Metabolic Pathways ◽  
Critical Role ◽  
Unknown Mechanism ◽  
C Elegans ◽  
Metabolic Remodeling ◽  
Wide Range ◽  
Exogenous Compounds ◽  
One Carbon Metabolism ◽  
Single Enzyme

Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, contrary to its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO enzymes. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and critical role in promoting health and longevity through metabolic remodeling.

scholarly journals Knockdown of ISOC1 inhibits the proliferation and migration and induces the apoptosis of colon cancer cells through the AKT/GSK-3β pathway

2019 ◽  
Vol 41 (8) ◽  
pp. 1123-1133 ◽  
Author(s):  
Bo Gao ◽  
Lianmei Zhao ◽  
Feifei Wang ◽  
Hanyu Bai ◽  
Jing Li ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Critical Role ◽  
Disease Free Survival ◽  
Clinical Samples ◽  
Colon Cancer Cells ◽  
And Migration ◽  
Gsk 3Β ◽  
Proliferation And Migration

Abstract Isochorismatase domain-containing 1 (ISOC1) is a coding gene that contains an isochorismatase domain. The precise functions of ISOC1 in humans have not been clarified; however, studies have speculated that it may be involved in unknown metabolic pathways. Currently, it is reported that ISOC1 is associated with breast cancer. In this research, the aim is to investigate the critical role of ISOC1 in colorectal cancer (CRC) and to explore its biological function and mechanism in colon cancer cells. In 106 paired clinical samples, we found that the levels of ISOC1 expression were widely increased in cancer tissues compared with matched adjacent non-tumor tissues and that increased expression of ISOC1 was significantly associated with tumor size, tumor invasion, local lymph node metastasis and Tumor, Node and Metastasis (TNM) stage. Moreover, higher expression levels of ISOC1 were correlated with shorter disease-free survival in patients 2 years after surgery. In vitro, ISOC1 knockdown inhibited the proliferation and migration and induced the apoptosis of colon cancer cells, and in vivo, the xenograft tumors were also inhibited by ISOC1 silencing. We also used MTS, Transwell and cell apoptosis assays to confirm that ISOC1 plays a critical role in regulating the biological functions of colon cancer cells through the AKT/GSK-3β pathway. Additionally, the results of confocal microscopy and western blot analysis indicated that ISOC1 knockdown could promote p-STAT1 translocation to the nucleus.

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